Zamora-Fuentes Jose María, Hernández-Lemus Enrique, Espinal-Enríquez Jesús
Computational Genomics Division, National Institute of Genomic Medicine, Mexico City, Mexico.
Centro de Ciencias de la Complejidad, Universidad Nacional Autónoma de Mexico, Mexico City, Mexico.
Front Genet. 2020 Nov 3;11:578679. doi: 10.3389/fgene.2020.578679. eCollection 2020.
Clear cell renal carcinoma (ccRC) is a highly heterogeneous and progressively malignant disease. Analyzing ccRC progression in terms of modifications at the molecular and genetic level may help us to develop a broader understanding of its patho-physiology and may give us a glimpse toward improved therapeutics. In this work, by using TCGA data, we studied the molecular progression of the four main ccRC stages (i, ii, iii, iv) in two different yet complementary approaches: (a) gene expression and (b) gene co-expression. For (a) we analyzed the differential gene expression between each stage and the control non-cancer group. We compared the progression molecular signature between stages, and observed those genes that change their expression patterns through progression stages. For (b) we constructed and analyzed co-expression networks for the four ccRC progression stages, as well as for the control phenotype, to observe whether and how the co-expression landscape changes with progression. We separated genomic interactions into intra-chromosome () and inter-chromosome (). Finally, we intersected those networks and performed functional enrichment analysis. All calculations were made over different network sizes, from the top 100 edges to top 1,000,000. We show that differential expression is quite similar between ccRC progression stages. However, interestingly, two genes, namely SLC6A19 and PLG show a significant progressive decrease in their expression according to ccRC stage, meanwhile two other genes, SAA2-SAA4 and CXCL13 show progressive increase. Despite the high similarity between gene expression profiles, all networks are substantially different between them in terms of their topological features. Control network has a larger proportion of interactions, meanwhile for any stage, the amount of interactions is higher, independent of the network cut-off. The majority of interactions in any network are phenotype-specific. Only 189 interactions are shared between the five networks, and 533 edges are ccRC-specific, independent of the stage. The small resulting connected components in both cases are formed by genes with the same differential expression trend, and are associated with important biological processes, such as cell cycle or immune system, suggesting that activity of these categories follows the differential expression trend. With this approach we have shown that, even if the expression program is similar during ccRC progression, the co-expression programs strongly differ. More research is needed to understand the delicate interplay between expression and co-expression, but this is a first approach to enclose both approaches in an integrative view aimed at a deeper understanding in gene regulation in tumor evolution.
透明细胞肾细胞癌(ccRC)是一种高度异质性且恶性程度不断进展的疾病。从分子和基因水平的修饰角度分析ccRC的进展,可能有助于我们更全面地了解其病理生理学,并有望为改进治疗方法提供线索。在这项研究中,我们利用TCGA数据,通过两种不同但互补的方法研究了ccRC四个主要阶段(i、ii、iii、iv)的分子进展:(a)基因表达和(b)基因共表达。对于(a),我们分析了每个阶段与对照非癌组之间的差异基因表达。我们比较了各阶段之间的进展分子特征,并观察那些在进展阶段改变其表达模式的基因。对于(b),我们构建并分析了ccRC四个进展阶段以及对照表型的共表达网络,以观察共表达格局是否以及如何随进展而变化。我们将基因组相互作用分为染色体内()和染色体间()。最后,我们对这些网络进行交集分析并进行功能富集分析。所有计算均针对不同的网络规模进行,从顶部100条边到顶部1,000,000条边。我们发现ccRC进展阶段之间的差异表达非常相似。然而,有趣的是,有两个基因,即SLC6A19和PLG,根据ccRC阶段显示其表达显著逐渐降低,同时另外两个基因SAA2 - SAA4和CXCL13显示逐渐增加。尽管基因表达谱之间高度相似,但所有网络在拓扑特征方面却有很大差异。对照网络中 相互作用的比例更大,与此同时,对于任何阶段, 相互作用的数量都更高,与网络截止值无关。任何网络中的大多数相互作用都是表型特异性的。五个网络之间仅共享189个相互作用,并且有533条边是ccRC特异性的,与阶段无关。在这两种情况下产生的小连通组件由具有相同差异表达趋势的基因形成,并与重要的生物学过程相关,如细胞周期或免疫系统,这表明这些类别的活性遵循差异表达趋势。通过这种方法我们表明,即使在ccRC进展过程中表达程序相似,但共表达程序却有很大差异。需要更多研究来理解表达与共表达之间的微妙相互作用,但这是将这两种方法纳入一个综合观点以更深入了解肿瘤进化中基因调控的第一步。